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Vol. 299, Issue 2, 593-602, November 2001
Department of Pharmacology, University of Texas Health Science
Center, San Antonio, Texas (K.A.B., B.D.S., W.P.C.); and Department of
Anesthesiology, Mount Sinai School of Medicine, New York, New York
(S.M.)
The serotonin (5-HT)2A and 5-HT2C receptors
share a high degree of sequence homology and have very similar
pharmacological profiles. Although it is generally believed that the
cellular signal transduction mechanisms activated by these receptors
are indistinguishable, recent data suggest significant differences in
their signaling cascades. In this study we explored differences in the
characteristics and mechanisms of rapid desensitization between the
5-HT2A and 5-HT2C receptor systems. For both
receptor systems, pretreatment with 5-HT reduced the ability of a
maximal concentration of 5-HT to stimulate phospholipase C-mediated
inositol phosphate accumulation by about 65%, although the
5-HT2C receptor system was more sensitive to the
desensitizing stimulus. Differences in the concentration dependence of
the rate constant for desensitization (kdes)
suggested different mechanisms of desensitization for the 5-HT2A and 5-HT2C receptor systems. At very
high receptor occupancy (>99%), the responsiveness of the
5-HT2A, but not the 5-HT2C, receptor system
returned to control levels despite the continued presence of the
agonist. This resensitization was dependent upon the activity of
protein kinase C (PKC). Agonist-induced desensitization of the
5-HT2A, but not the 5-HT2C, receptor system was
reduced by the PKC inhibitors staurosporine and bisindolylmaleimide,
and by down-regulation of PKC. In addition, inhibitors of calmodulin (W-7) or of calmodulin-dependent protein kinase II, reduced
5-HT2A, but not 5-HT2C, desensitization.
Desensitization of the 5-HT2C, but not the
5-HT2A, receptor system was dependent on G protein receptor
kinase activity. These data further emphasize the major differences in
the signaling systems coupled to 5-HT2A/2C receptors.
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